Submissions for variant NM_004333.6(BRAF):c.1783T>C (p.Phe595Leu)

dbSNP: rs794729219

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414439	SCV000491004	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F594L); This variant is associated with the following publications: (PMID: 22142829, 24803665, 37039257, 33683002, 28856074, 34573299, 31060855, 32913992, 18039235, MelchorL2015[Abstract], 31573083, 33128510, 29533785, 19206169, 20186801, 18042262, 21871821, 22495831, 29084544, 23093928, 35226061, 33198372, 34331515, 36448195, 26826419, 37530550, 26582644, 16439621, 15035987, 25463315, 24957944, 15488754, 15520807, 17603483, 29493581)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000184039	SCV000781087	likely pathogenic	Cardiofaciocutaneous syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222430	SCV002500808	pathogenic	Cardio-facio-cutaneous syndrome	2022-03-31	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1783T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Ciara_2015, Matalon_2021), and in one case the de novo occurrence of the variant was confirmed. In addition two equivalent missense variants (c.1785T>A (p.F595L) and c.1785T>G (p.F595L)) have also been reported in patients affected with Cardio-facio-cutaneous syndrome (HGMD). These data indicate that the variant is likely associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in low to intermediate Braf kinase activity, which works cooperatively with Ras leading to increased MEK/ERK signaling (Kordes_2016, Yao_2017, Ng_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516942	SCV003516832	pathogenic	RASopathy	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 18042262, 19206169, 20186801, 21871821, 22495831, 23093928, 25463315, 29084544). In at least one individual the variant was observed to be de novo. This variant is also known as F594L. ClinVar contains an entry for this variant (Variation ID: 202193). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 26582644). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000184039	SCV000236570	pathogenic	Cardiofaciocutaneous syndrome 1	2013-11-06	no assertion criteria provided	clinical testing
Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca	RCV002291588	SCV002584889	uncertain significance	Prostate cancer, hereditary, 1	2022-07-29	no assertion criteria provided	clinical testing